Serotonin (5-hydroxytryptamine, 5-HT) elicits a multitude of physiological effects through the interaction with at least fourteen receptors that have been grouped on the basis of molecular, pharmacological, and functional criteria into seven discrete families (5-HT1-7) [1]. The 5-HT7 receptor was identified starting from 1993 by the application of targeted molecular biology techniques. It has been described in various species and remains the last 5-HT receptor to be discovered. The 5-HT7 receptor has been localized in discrete areas of the brain and in the periphery. Within the central nervous system this receptor has been detected in high levels in the thalamus, hippocampus, and hypothalamus (especially within the suprachiasmatic nucleus, SCN) [2]. Much information is available on the pathophysiological role of 5-HT7 receptor in the central nervous system. The availability of the selective 5-HT7 antagonist SB-269970 and of 5-HT7-knockout mice has allowed relevant insight into the role of 5-HT7 receptors in depression. As an example, pharmacological blockade of 5-HT7 receptor or inactivation of the receptor gene leads to an antidepressant-like behavioral profile in rodent models of depression (forced swim test and tail suspension test) [3]. Recently, it has been suggested that the atypical antipsychotic drug amisulpride exerts its antidepressant action through blockade of 5-HT7 receptors [4]. It should also be noted that the atypical antipsychotic aripiprazole has high affinity for the 5-HT7 receptor [5,6] and it is successfully used to augment the effect of traditional antidepressants [7]. These findings further support the potential of 5-HT7 receptor antagonists to yield a novel class of antidepressant drugs. The recent availability of selective agonists such as AS-19 and E-55888 is opening up new scenarios on the therapeutic actions of 5-HT7 receptor activation. It has been demonstrated that behavioral antinoception can be achieved by systemic administration of AS-19 or E-55888 [8]. Also, AS-19 has served to demonstrate the involvement of 5-HT7 receptor in memory formation [9]. In addition, it has been found that the stimulation of cultured striatal neurons with the mixed 5-HT1A/7 agonist, 8-OH-DPAT, induced a marked neurite outgrowth. This effect was specifically triggered by 5-HT7 receptor activation, because it was blocked by application of SB-269970 [10]. These data supported the crucial role of this receptor in the modulation of neuronal morphology, as also observed in mouse hippocampal neurons following 5-HT7 receptor activation [11].
The international application WO2008146064A1 disclosed some benzofuran compounds that bind 5-hydroxy triptamine-7 receptor for use in the treatment or prevention of disorders of central nervous system and/or cardiovascular disorders.
The compounds reported in the state of the art with high affinity for the 5-HT7 receptor suffer from the lack of selectivity over a range of 5-HT receptors. Also, the most potent 5-HT7 ligands proposed to date are not sufficiently metabolically stable. This precludes the use of such compounds as in vivo tools for studying the function of 5-HT7 receptor and as drugs. Moreover, to date no positron emission tomography tracer is available to visualize 5-HT7 receptor in either central nervous system or periphery.